From a Contributing Editor

For individuals with schizophrenia who are failed by trials of single antipsychotics, what’s next?

This week, we discuss a paper that addresses a treatment controversy. Antipsychotic polypharmacy (the use of more than one antipsychotic) is generally discouraged because the efficacy evidence is weak, and there is risk of increasing adverse events and effects with the addition of a second antipsychotic. Choosing Wisely is an initiative that seeks to advance a national dialogue on avoiding unnecessary medical tests, treatments and procedures; among their psychiatric recommendations is to avoid the use of multiple antipsychotics. The American Psychiatric Association contributed this to the Choosing Wisely initiative:

Research shows that use of two or more antipsychotic medications occurs in 4 to 35% of outpatients and 30 to 50% of inpatients. However, evidence for the efficacy and safety of using multiple antipsychotic medications is limited, and risk for drug interactions, noncompliance and medication errors is increased. Generally, the use of two or more antipsychotic medications concurrently should be avoided except in cases of three failed trials of monotherapy, which included one failed trial of Clozapine where possible, or where a second antipsychotic medication is added with a plan to cross-taper to monotherapy.

 This is where this week’s selection comes in. The study, “Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia,” is from Finland by Karolinska Institutet’s Jari Tiihonen and his colleagues. This paper uses Finnish population-based health administrative data to evaluate the association between antipsychotic polypharmacy and psychiatric hospitalization. They conclude: “These results indicate that rational antipsychotic polypharmacy seems to be feasible by using 2 particular antipsychotics with different types of receptor profiles.”

kakslauttanen_aurora_augustFinland: home to big Northern Lights (and big databases)

In this Reading, we consider this paper and wonder if it should change our prescribing choices.

Paul Kurdyak, MD, PhD, FRCPC


Schizophrenia and Medications

“Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia”

Jari Tiihonen, Heidi Taipale, Juha Mehtälä, Pia Vattulainen, Christoph U. Correll, Antti Tanskanen

JAMA Psychiatry, 20 February 2019  Online First

Antipsychotic polypharmacy is used among up to 30% of patients with schizophrenia. The use of antipsychotic polypharmacy has raised concern owing to the lack of evidence for its efficacy and safety as well as variable justifications and practice patterns. Meta-analyses of randomized clinical trials (RCTs) have shown mixed results, possibly because of shortcomings owing to low number of participants and lacking separations of high- vs low-quality studies. The most-recent meta-analysis without these limitations concluded that data from high-quality studies show beneficial outcomes only for negative symptom reduction with aripiprazole augmentation. Short-term symptom reduction, used as the primary outcome in RCTs, is an important measure for effectiveness of antipsychotic treatment. However, schizophrenia is a lifelong illness, and long-term outcome, including relapse prevention and avoidance of adverse physical morbidity and mortality effects owing to long-term antipsychotic load, is an even more important issue for the patients’ well-being. Conducting an RCT on these outcomes would require several thousands of patient-years, which is probably the reason why no such studies have been done.

Observational studies can overcome this problem by using large electronic databases. Results from 1 large observational study have shown that any antipsychotic polypharmacy was associated with an approximately 40% lower risk of rehospitalization and death compared with any monotherapy, but the major problem in observational studies is residual confounding related to selection bias. This limitation can be eliminated by using within-individual analyses in which each patient is used as his or her own control. To our knowledge, no observational study has been published on the comparative effectiveness of antipsychotic combinations vs monotherapies using this method. We aimed to study this issue, using within-individual analyses, in a nationwide cohort including all patients with schizophrenia in Finland.

tiihonenJari Tiihonen

So begins a new study by Tiihonen et al., examining the relative likelihood of psychiatric hospitalizations when individuals are prescribed two versus one antipsychotic.

Here’s what they did:

  • They used population-based health administrative data from Finland.
  • They identified all individuals with a diagnosis of schizophrenia from inpatient settings from 1996 to 2015 (individuals could have had a prevalent diagnosis of schizophrenia from as early as 1972).
  • Drug use was measured from 1995 to 2015.
  • The primary outcome was psychiatric rehospitalization, and psychiatric hospitalization rates prior to the addition of a second antipsychotic were compared to rates after within the same individual (as opposed to, say, comparing those who took the medication with those who didn’t).
  • The within-individual comparison is important because the authors argue that this takes into account systematic differences that would occur if they were to compare indivduals on multiple antipsychotics to individuals on monotherapy.
  • The statistical analysis is complex, but essentially they use Cox Proportional Hazard modeling to measure time to psychiatric hospitalization to compare rates pre- and post-polypharmacy.

Here’s what they found:

  • The cohort was very large and included 62 250 patients, among whom 50% were men.
  • Rehospitalization following cohort entry was common over the median 14 years per subject of follow-up, with 59% (N = 36 631) of the prevalent cohort and 58% (N = 5 045) of the incident, or first episode, cohort experiencing a psychiatric rehospitalization.
  • A total of 67.2% (n = 41 812) of the patients in the total cohort and 54.1% (n = 4717) of those in the incident cohort used antipsychotic polypharmacy during the follow-up, and 57.5% (n = 35 793) of the prevalent cohort and 41.6% (n = 3 627) of the incident cohort were exposed to antipsychotic polypharmacy for at least 90 days.
  • With only a few exceptions, the use of antipsychotics reduced psychiatric hospitalizations compared to periods of time of no antipsychotic use within individuals.
  • Certain antipsychotic combinations appear to reduce the risk of psychiatric hospitalization compared to monotherapy:
    • Clozapine plus aripiprazole compared to clozapine alone,
    • Aripiprazole plus clozapine compared to aripiprazole alone,
    • Olanzapine plus any long-acting injectable (LAI) or olanzapine plus clozapine compared to olanzapine alone,
    • Risperidone plus clozapine, olanzapine or quetiapine compared to risperidone alone,
    • Any antipsychotic plus quetiapine vs. quetiapine alone,
    • Any LAI plus olanzapine compared to LAI alone.

They note:

To our knowledge, this is the first study on the long-term use of antipsychotic polypharmacy in schizophrenia. It is nearly impossible to conduct an RCT including tens of thousands of patient-years to achieve sufficient statistical power. Therefore, observational studies are the only way to investigate long-term comparative outcomes. The major shortcoming in observational studies is selection bias, because treatments are not chosen on a random basis. In this study, we used within individual analyses in which each patient is used as his or her own control to minimize selection bias.

A few thoughts:

  1. This is an important paper because it addresses an important problem: how to adequately treat individuals with schizophrenia who are treatment-refractory?
  1. Both the problem (being treatment-refractory) and the adverse outcome of this study (psychiatric rehospitalization) are very common.
  1. The authors make the case for using observational methods because an adequately powered RCT with sufficient follow-up will likely never be funded to study this issue.
  1. The use of within-individual methods to explore outcomes pre- and post-exposure is an important way to minimize bias from systematic differences between exposed and unexposed because there is minimal variation when the exposed and unexposed periods occur in the same individual.
  1. However, there are other issues to consider in using this method that could result in antipsychotic polypharmacy looking favourable compared to monotherapy.
  1. The main issue has to do with circumstances that would predispose a patient and his/her prescribing physician to consider antipsychotic polypharmacy – this decision does not occur randomly, but in response to some event such as a relapse prompting polypharmacy.
  1. As such, there may be simple regression to the mean occurring that would appear to favour the addition of an antipsychotic.
  1. Or it could be that there is a more systematic response to relapse (better follow-up, more intensive non-pharmacologic treatment that is unmeasured in this study) that could be happening concurrently with antipsychotic polypharmacy.
  1. Within-individual comparisons are unable to account for these issues.

At the end of the day, how should one respond to the findings of this paper? Even if one ignores the possible methodological issues highlighted in points 6 through 8, the findings are unlikely to change pharmacological management. Moreover, the authors include medical hospitalizations as a proxy for adverse events associated with antipsychotic exposure, but that would not detect the vast majority of metabolic syndrome, movement disorder, or other adverse effects. Indeed, the study does not have much to say about balancing the need to prevent relapse with the increased risk of adverse events associated with polypharmacy, focusing instead on relapse prevention using psychiatric hospitalization as a proxy measure. The advice of Choosing Wisely is probably “wise” to follow, recommending two trials of antipsychotic monotherapy, followed by clozapine monotherapy before antipsychotic polypharmacy is considered. And antipsychotic polypharmacy should be restricted to clozapine plus another antipsychotic. Here, the study would suggest that aripiprazole is a good antipsychotic to consider for the individuals with schizophrenia who are treatment refractory to clozapine monotherapy. And, of course, LAIs will always be useful for individuals who struggle with treatment adherence.


Reading of the Week. Every week we pick articles and papers from the world of Psychiatry.